During the previous funding cycle of the Wake Forest Center for Botanical Lipids, we demonstrated that Echium oil (EO), a botanical oil enriched in stearidonic acid (18:4 w3), the immediate downstream product of the rate-limiting delta-6 desaturation of alpha-linolenic acid (18:3 w3), reduces plasma lipids, inflammation, and atherosclerosis as well as fish oil (FO), but we do not know the exact mechanisms for the protection. EO also contains 11% gamma-linolenic acid (GLA, 18:3 w6), which is the delta-6 desaturation product of linoleic acid (18:2 w6) and thus, can provide substrate for conversion to anti-inflammatory series 1 prostaglandin (PGEI). However, we do not know whether a botanical oil that is enriched in GLA, such as borage oil (BO; 25% GLA), is equally protective or less protective than EO. The goal of project 1 in the renewal application is to investigate whether EO and BO are equally atheroprotective and to determine anti-atherogenic mechanisms ofthese botanical oils. Our primary hypothesis is that both EO and BO will reduce atherosclerosis relative to palm oil (PO), by attenuating the rise of proinflammatory monocytes in blood and the trafficking of monocytes into atherosclerotic lesions (specific aim 1). Furthermore, we hypothesize that EO and BO will result in alternative activation of macrophages, relative to PO, resulting in less inflammatory macrophages (specific aim 2). Finally, we propose that the polyunsaturated fatty acid (PUFA)-induced macrophage alternative activation will occur through multiple mechanisms that include antagonism of proinflammatory gene transactivation, PPARgamma-dependent transactivation of anti-inflammatory genes, and PPARgamma-dependent transrepression of pro-inflammatory genes (specific aim 3). The proposed mechanistic studies should allow us to determine the best botanical oils or combinations to move into human trials to test for reduction of atherosclerosis risk and inflammation and to improve our basic information regarding the mechanism of action of botanical oils in chronic disease prevention.